Synergistic effects of blending multiple additives in UHMWPE

ABSTRACT

Oxidation resistant crosslinked ultrahigh molecular weight polyethylene (UHMWPE) is described, wherein at least two different additives in the manufacture synergistically increase the oxidation resistance of crosslinked UHMWPE. This allows the manufacture of oxidation resistant crosslinked UHMWPE using lower levels of additives and/or lower levels of crosslinking irradiation or chemicals. The lower levels of additives and/or crosslinking produce crosslinked UHMWPE having desired physical properties not possible without the synergistic interaction of the additives. This crosslinked UHMWPE may be used in medical prostheses such as in bearing components having desired physical properties such as wear resistance and oxidation resistance not possible without the synergistic interaction of the additives.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.14/180,933 filed Feb. 14, 2014 and issuing as U.S. Pat. No. 9,156,963,which is a continuation of U.S. patent application Ser. No. 13/318,731filed Nov. 3, 2011 and issued as U.S. Pat. No. 8,653,154, which is aU.S. national stage filing of International Application No.PCT/US2010/033494 filed May 4, 2010, which claims the benefit of U.S.Provisional Patent Application No. 61/175,308 filed May 4, 2009, theentire contents of each application hereby incorporated herein byreference in its entirety.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to oxidation resistant polymers, includingtheir manufacture and use. This includes as a nonlimiting exampleoxidation resistant crosslinked ultra-high molecular weight polyethylene(UHMWPE). This invention further relates to the use of polymers,including oxidation resistant crosslinked UHMWPE, in artificial bodymembers, including medical prosthesis containing or made from one ormore of such polymers. Nonlimiting examples include medical prosthesesfor replacing joints, such as hip and knee joints, wherein a polymer,such as oxidation resistant UHMWPE forms a bearing part of the joint,including providing a surface for articulating members of the joint. Ina nonlimiting example, one portion of a medical prosthesis contains apolymer bearing that forms a surface, such as an acetabular surface,against which another portion of the medical prosthesis, such as aball-like portion made of metal or ceramic, articulates against thebearing surface during use of the joint in a body.

BACKGROUND OF THE INVENTION

Prosthetic implants in arthroplasty, such as artificial knee and hipimplants, typically involve the articulation of either a metal orceramic ball shaped component, which is typically part of one half of ajoint, against a polymer, such as UHMWPE, which is typically the otherhalf of a joint, and is in the shape of a concave receptacle forreceiving the articulation of the ball shaped component. More than adecade ago, it was discovered that exposure of the UHMWPE to ionizingradiation crosslinks the material and results in dramatically improvedwear resistance. In contrast, the ionizing radiation also results inchain scission of the polymer chains and the creation of long-lived freeradicals in the material. If these free radicals are not extinguished,they react with oxygen and result in oxidation of the polymer andsubsequent degradation of the mechanical and tribological properties. Toextinguish the free radicals, a post-irradiation heat treatment iscommonly conducted.

Heating the crosslinked polymer above the melting temperature (i.e.,re-melting) has been shown to extinguish all of the measurable freeradicals in the crosslinked material and stabilize it against oxidation.On the other hand, re-melting also results in a decrease incrystallinity because the reduced mobility of the crosslinked chainsinhibits the folding of the chains into crystalline lamella, whichresults in decreased yield and ultimate tensile strengths.

Alternatively, the crosslinked polymer can be heated to a temperaturebelow the melting temperature (i.e., sub-melt annealing). Because thelarger crystalline lamella are not melted during sub-melt annealing, thecrystallinity is typically either maintained or increased, whichtypically maintains or improves the yield strength and leads to less ofa decease in the ultimate tensile strength of the resultant material. Incontrast, the choice of a sub-melt heat treatment leaves a measurableamount of free radicals in the unmelted crystalline regions of thematerial that can migrate out and oxidize with time.

As a result of these trade-offs, a method of stabilizing the highlycrosslinked UHMWPE against oxidation without compromising the mechanicalproperties is desirable.

The blending of a UHMWPE resin with an antioxidant has been used tonegate the need for a post-irradiation heat treatment and the subsequenttrade-offs inherent to those methods. This approach blends a singleantioxidant with the resin, and the blend is then consolidated bystandard techniques, such as by compression molding or ram extrusion.This consolidated blend is then exposed to ionizing radiation tocrosslink the material and improve the wear resistance. The blendedantioxidant operates as a free-radical scavenger and interrupts theoxidation pathway by readily donating a hydrogen (H) atom to the damagedpolymer chain and, in turn, taking on the free radical to form a stablefree radical that it does not react with oxygen. Because apost-irradiation heat treatment may not be necessary for the removal offree radicals with this particular method, the mechanical properties arenot degraded to the same extent.

On the other hand, there are two problems inherent to this blendingmethod. First, each antioxidant molecule is capable of donating a finitenumber of hydrogen atoms/quenching or extinguishing a finite number offree radicals. For example, it has been theorized that each vitamin Emolecule is capable of quenching two free radicals. As a result, theconsumption of the antioxidant during the scavenging of free radicalscould limit the effective time of protection against oxidation. Forexample, if the concentration of the antioxidant is too low, all of thefree-radical-quenching ability could be consumed prior to theextinguishing of all of the free radicals, which would result inremaining free radicals that could react with oxygen and causeoxidation. From this prospective, it is preferable to have a highconcentration of antioxidant to insure that all of it is not consumedprior to the capture of all of the free radicals and to maximize thelong-term oxidation resistance. On the other hand, increasing theconcentration of the antioxidant beyond a certain limit can result in asupersaturation that can cause elution or diffusion of the antioxidantout of the polyethylene. The result of this elution could be undesirableinteractions of the antioxidant with the human body or depletion of theantioxidant remaining at the surfaces of the material.

Second, the improved wear resistance of the irradiated polymer isdependent upon the generation of free radicals by ionizing radiation andthe subsequent combination of the free radicals to form chemical bonds(i.e., crosslinks) between polymer chains. The presence of anantioxidant during irradiation scavenges some of these free radicals andresults in an undesired inhibition of crosslinking. As a result, higherirradiation doses are necessary to produce an equivalent level of wearresistance compared to an antioxidant-free polymer. As a consequence ofincreasing the irradiation dose to overcome the inhibition ofcrosslinking, the ductility and the toughness of the crosslinkedmaterial decrease even further. From this prospective, it is preferableto minimize the concentration of antioxidant to minimize the inhibitionof crosslinking and the necessary irradiation dose to achieve a givenwear resistance.

U.S. Pat. Nos. 7,431,874 and 7,498,365, each patent herein incorporatedby reference, disclose a method to avoid these problems with blending.According to this method, the UHMWPE is consolidated and irradiatedprior to the introduction of vitamin E (Vit E) into the material throughdiffusion. Because the material does not contain an antioxidant at thetime of irradiation, there is no inhibition of crosslinking. Becauseinhibition is not a concern, the concentration of Vit E in the polymercan be increased to insure that there is a more than adequate amount ofantioxidant to quench all of the existing free radicals and providelong-term oxidation resistance.

The negative aspects of this diffusion method are related to the timeand expense necessary to diffuse a sufficient quantity of Vit E into thematerial and homogenize the concentration throughout the component. Inaddition, the higher concentrations of Vit E typically utilized in thisprocess lead to a large concentration gradient, which could result inelution or diffusion of the Vit E out of the polyethylene and depletionof the antioxidant at the surface.

The combination of synergistic antioxidants and their effects onfree-radical quenching and antioxidant “regeneration” or “recycling” hasbeen considered in the past, but never related to medical uses,including in medical prostheses. For example, it has been demonstratedin the literature that the regeneration of Vit E takes place in vivothrough chemical reactions with other molecules such as ascorbic acid(vitamin C). As a result of this interaction, the Vit E molecule is“recharged” and can theoretically quench 2 more free radicals. Thisprocess could proceed ad infinitum to provide long-term oxidationresistance with a low concentration of an antioxidant. Similar in-vivoregeneration of curcumin by a synergistic molecule has been theorizedbased on oncology research. In the polymeric sciences, the combinationsof Vit E with a phosphate antioxidant or Vit E with polyhydric alcoholboth reduce changes in color and promote higher retention of the Vit Eduring melt processing of polypropylene through a similar synergisticmechanism.

All of the efforts in the prior art related to UHMWPE have been to blendonly one antioxidant into the UHMWPE. Moreover, EP Published PatentApplication No. EP2047823 A1, for example, specifically states that “oneantioxidant is preferred” for “economical and efficiency sake.” Theproblem with the incorporation of a single antioxidant is that it is atleast partially consumed during processing, during the quenching of freeradicals after processing and during use/service. As a result, the priorart composition requires a higher concentration of antioxidant to insurethat there is enough antioxidant to protect the medical device againstlong-term oxidation for the duration of the service life. This need fora higher concentration of a single antioxidant also results ininhibition of crosslinking, the need for higher irradiation doses toachieve a given wear resistance and, ultimately, leads to degradedmechanical properties.

BRIEF SUMMARY OF THE INVENTION

The present invention relates to the discovery that adding two or moreadditives to crosslinked UHMWPE improves the oxidation resistance of thematerial more than the additive effect of the two additives alone (i.e.,synergistically). This discovery relates to at least the process ofpreparing oxidation resistant UHMWPE by adding two or more differentantioxidants or additives to UHMWPE, medical prostheses made using thisoxidation resistant UHMWPE, and the use of such medical prostheses inpatients in need of such medical prostheses.

Examples of several potential processing routes for the invention areshown in FIG. 1. The invention includes a composition of a medicaldevice in which combinations of select additives and/or antioxidantssolve one or both of the aforementioned problems currently associatedwith the blending of a single antioxidant and inadequate crosslinkingthat can deteriorate the tribological performance of UHMWPE.

The invention includes blending of select, synergisticadditives/antioxidants with another antioxidant into UHMWPE toregenerate or recycle the antioxidant and avoid the consumption of theantioxidant during free-radical scavenging, which would also permit theproduction of a medical device with lower concentrations of antioxidantsthat not only achieves higher oxidation resistance but also produces ahighly wear-resistance surface. Furthermore, a lower concentration ofantioxidant could lead to less inhibition of crosslinking upon exposureto radiation, which reduces the need for higher irradiation doses toachieve a given wear resistance and, in turn, leads to less degradationof the mechanical properties. Alternatively, this invention has improvedoxidation resistance in comparison to prior devices even though it has asimilar concentration of antioxidants.

Additionally, this invention has an advantage over the prior art in thatthe preservation of the antioxidant during consolidation/processing aswell as a reduction of changes in UHMWPE color during processing and/orservice.

One embodiment of the present invention comprises a process forpreparing crosslinked oxidation resistant UHMWPE for use in medicalprostheses comprising the steps of: (i) obtaining UHMWPE resin; (ii)combining the UHMWPE resin with both a first amount of a first additiveand a second amount of a second additive, wherein the first and thesecond additives are different additives; (iii) consolidating the UHMWPEthat has been combined with the first and second additives; and (iv)crosslinking the consolidated UHMWPE to create oxidation resistantUHMWPE.

In certain embodiments, the UHMWPE resin is crosslinked, for example byirradiation or chemical crosslinking, prior to being combined with theat least first and/or second additives.

In certain embodiments, the crosslinking of the UHMWPE is by irradiationcrosslinking or by chemical crosslinking.

In still further embodiments of the invention, the synergistic effect onoxidation resistance by the combination of at least a first and at leasta second additive allows for the amount of the first and/or the secondadditives to be lowered to achieve, for example, the same level ofoxidation resistance as would have been achieved by a higherconcentration of either additive alone.

Still further, in certain embodiments, due to the lower amount of the atleast first and/or at least second additive in the UHMWPE, the dose ofirradiation or chemical crosslinking can be reduced compared to whatwould be required if a single additive were present, because the lowerconcentration of antioxidant additives in the UHMWPE of the inventionallows crosslinking at a lower dose as there are fewer additives tointerfere with crosslinking.

In additional embodiments of the invention, the amount of the firstadditive that is combined with the UHMWPE resin in step (ii) (above) isabout 50 ppm to about 5,000 ppm, more preferably about 50 ppm to about2,000 ppm, still more preferably about 100 ppm to about 1,000 ppm, andfurther preferably about 200 ppm to about 800 ppm, based on the relativeamount of the UHMWPE, and the amount of the second additive that iscombined with the UHMWPE resin in step (ii) (above) is about 50 ppm toabout 5,000 ppm, more preferably about 50 ppm to about 2,000 ppm, stillmore preferably about 100 ppm to about 1,000 ppm, and further preferablyabout 200 ppm to about 800 ppm, based on the relative amount of theUHMWPE.

In other embodiments of the invention, the amount of the first additivethat is combined with the UHMWPE resin in step (ii) (above) is about0.005 wt. % to about 0.5 wt. %, based on the relative amount of theUHMWPE, and the amount of the second additive that is combined with theUHMWPE in step (ii) is about 0.005 wt. % to about 0.5 wt. %, based onthe relative amount of the UHMWPE.

More particularly, in certain embodiments where the crosslinking is doneby irradiation, the dose of the crosslinking is about 1.5 MRad to about30 MRad, more preferably about 2.5 MRad to about 15 MRad, and morepreferably still about 2.5 MRad to about 12 MRad.

In other embodiments, after the oxidation resistant UHMWPE has been madeas described above (combined with two or more additives, consolidated,and crosslinked), it is further machined into a bearing component foruse in a medical prosthesis.

In certain embodiments, the crosslink densities of the combined,consolidated, and crosslinked UHMWPE, as well as that of a bearingcomponent made from such are about 0.03 mol/dm³ to about 0.50 mol/dm³.

In more embodiments, including in those discussed above, the firstadditive is selected from the group consisting of phenolic antioxidantsand hindered amines, and the second additive is selected from the groupconsisting of phosphorous additives, polyhydric alcohols, phenolicantioxidants, hindered amines, carotenoids, amino-acid-based additives,thiosynergists, and acid antioxidants.

Still further, in embodiments including those discussed above, thephenolic antioxidants of the first additive are selected from the groupconsisting of tocopherols, tocotrienols, curcuminoids, flavonoids,phenylpropanoids, and synthetic phenolic antioxidants; the hinderedamine antioxidants of the first additive are selected from the groupconsisting of chimassorb 944, chimassorb 119 FL, cyasorb UV 3346,tinuvin 144, tinuvin 765, tinuvin 770 DF; the phosphorous additives ofthe second additive are selected from the group consisting ofphosphites, phosphonites, and phosphines; the polyhydric alcohols of thesecond additive are selected from the group consisting ofdipentaerythritol, tripentaerythritol, and trimethylolpropaneethoxylate; the phenolic antioxidants of the second additive areselected from the group consisting of tocopherols, tocotrienols,curcuminoids, flavonoids, phenylpropanoids synthetic antioxidants, andbenzoquinols; the hindered amines of the second additive are selectedfrom the group consisting of chimassorb 944, chimassorb 119 FL, cyasorbUV 3346, tinuvin 144, tinuvin 765, tinuvin 770 DF; the carotenoids ofthe second additive are selected from the group consisting ofbeta-carotene, lycopene, lutein, zeaxanthin, echinenone, and zeaxanthin;the amino-acid-based additives of the second additive are selected fromthe group consisting of glutathione, cystein, tyrosine, and tryptophan;the thiosynergists of the second additive are selected from the groupconsisting of distearyl thiodipropionate, irganox PS 800, and irganox PS802; and the acid antioxidants of the second additive are selected fromthe group consisting of ascorbyl palmitate, ascorbate, and lipoic acid.

Still further, in embodiments of the invention, including for examplethose nonlimiting examples discussed above, the tocopherols of the firstadditive are selected from the group consisting of dl-alpha-tocopherol,alpha-tocopherol, delta-tocopherol, gamma-tocopherol, andbeta-tocopherol; the tocotrienols of the first additive are selectedfrom the group consisting of alpha-tocotrienol, beta-tocotrienol,gamma-tocotrienol, and delta-tocotrienol; the curcuminoids of firstadditive are selected from the group consisting of curcumin,demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin,hexahydrocurcumin, curcumin sulphate, curcumin-glucuronide,hexahydrocurcumin, and cyclocurcumin; the flavonoids of the firstadditive are selected from the group consisting of naringenin,quercetin, hesperitin, luteolin, catechins, anthocyanins; thephenylpropanoid of the first additive is eugenol; the synthetic phenolicantioxidants of the first additive are selected from the groupconsisting of irganox 1010, irganox 1076, irganox 245, butylatedhydroxytolunene, and butylated hydroxyanisole; the phosphites of thesecond additive are selected from the group consisting of ultranox U626,hostanox PAR24, irgafos 168, Weston 619, and irgafox 126; thephosphonate of the second additive is sandostab P-EPQ; the phosphine ofthe second additive is pepfine; the tocopherols of the second additiveare selected from the group consisting of dl-alpha-tocopherol,alpha-tocopherol, delta-tocopherol, gamma-tocopherol, andbeta-tocopherol; the tocotrienols of the second additive are selectedfrom the group consisting of alpha-tocotrienol, beta-tocotrienol,gamma-tocotrienol, and delta-tocotrienol; the curcuminoids of secondadditive are selected from the group consisting of curcumin,demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin,hexahydrocurcumin, curcumin sulphate, curcumin-glucuronide,hexahydrocurcumin, and cyclocurcumin; the flavonoids of the secondadditive are selected from the group consisting of naringenin,quercetin, hesperitin, luteolin, catechins, and anthocyanins; thesynthetic antioxidants of the first additive are selected from the groupconsisting of irganox 1010, irganox 1076, irganox 245, butylatedhydroxytoluene, and butylated hydroxyanisole; and the benzoquinol of thesecond additive is selected from the group consisting of ubiquinol andcoenzyme Q10.

Additionally, in embodiments of the invention, including for examplethose discussed above, the catechins of the first additive are selectedfrom the group consisting of epigallocatechin gallate, epigallocatechin,epicatechin gallate and epicatechin; the anthocyanins of the firstadditive are selected from the group consisting of cyanidin,delphinidin, malvidin, peonidin, petunidin, and pelargonidin; thecatechins of the second additive are selected from the group consistingof epigallocatechin gallate, epigallocatechin, epicatechin gallate andepicatechin; and the anthocyanins of the second additive are selectedfrom the group consisting of cyanidin, delphinidin, malvidin, peonidin,petunidin, and pelargonidin.

In preferred embodiments, the oxidation resistant UHMWPE is madeaccording to the embodiments described above, including combining afirst and a second additive with UHMWPE resin, consolidating thecombined material, and crosslinking the consolidated UHMWPE, the firstadditive is a phenolic antioxidant and the second additive is acurcuminoid. Still further, preferred embodiments include the abovedescribed wherein the first additive is dl-alpha-tocopherol and thesecond additive is curcumin.

In still other preferred embodiments, the oxidation resistant UHMWPE ismade according to the embodiments described above, including combining afirst and a second additive with UHMWPE resin, consolidating thecombined material, and crosslinking the consolidated UHMWPE, the firstadditive is a phenolic antioxidant and the second additive is acurcuminoid. Still further, preferred embodiments include the abovedescribed method wherein the first additive is dl-alpha-tocopherol andthe second additive is curcumin. In other preferred embodiments furtherto those described above, the first additive is dl-alpha-tocopherol andthe second additive is dipentaerythritol. In still further preferredembodiments, in the above embodiments, the first additive is curcuminand the second additive is dipentaerythritol.

In still further preferred embodiments, the UHMWPE resin and the firstand second additives are combined as described above, the combination isconsolidated as described herein, and the UHMWPE is irradiated, andwherein the first additive is dl-alpha-tocopherol and it is combinedwith the UHMWPE resin at about 250 ppm, based on the relative amount ofthe UHMWPE and the second additive is curcumin and it is combined withthe UHMWPE at about 250 ppm, based on the relative amount of the UHMWPE,and the consolidated UHMWPE is crosslinked by irradiation at a dose ofabout 10 MRad.

In other preferred embodiments, the UHMWPE resin and the first andsecond additives are combined as described above, wherein the firstadditive dl-alpha-tocopherol is combined with the UHMWPE at about 300ppm, based on the relative amount of the UHMWPE; the second additivecurcumin is combined with the UHMWPE at about 300 ppm, based on therelative amount of the UHMWPE; and the crosslinking is by irradiation ata dose of about 10 MRad.

In still other preferred embodiments, the oxidation resistant UHMWPE ismade according to the embodiments described above, including combining afirst and a second additive with UHMWPE resin, consolidating thecombined material, and crosslinking the consolidated UHMWPE, the firstadditive is curcumin and the second additive is a dipentaerythritol.

In still further preferred embodiments, the UHMWPE resin and the firstand second additives are combined as described above, the combination isconsolidated as described herein, and the UHMWPE is irradiated, andwherein the first additive is curcumin and it is combined with theUHMWPE resin at about 300 ppm, based on the relative amount of theUHMWPE and the second additive is dipentaerythritol and it is combinedwith the UHMWPE at about 300 ppm, based on the relative amount of theUHMWPE, and the consolidated UHMWPE is crosslinked by irradiation at adose of about 10 MRad.

In other preferred embodiments, the UHMWPE resin and the first andsecond additives are combined as described above, wherein the firstadditive dl-alpha-tocopherol is combined with the UHMWPE at about 300ppm, based on the relative amount of the UHMWPE; the second additivecurcumin is combined with the UHMWPE at about 300 ppm, based on therelative amount of the UHMWPE; and the crosslinking is by irradiation ata dose of about 10 MRad.

Other preferred embodiments of the invention include a medicalprosthesis comprising a bearing component comprising crosslinked UHMWPEmade by any of the processes of making oxidation resistant UHMWPEsummarized above and described in detail below. Moreover, in preferredembodiments, the medical prosthesis having the bearing made according tothe processes of this invention may be a joint prosthesis, such as butnot limited to a hip, knee, or finger joint prosthesis.

In other embodiments of the present invention, medical prostheses havingbearing components of crosslinked oxidation resistant UHMWPE madeaccording to the methods summarized above and described in detail below,can be administered to patients in need of such prostheses, includingartificial hip and joint prosthetics.

In other embodiments of the present invention, the first and/or secondadditives are added to the UHMWPE in manners other than strictly bycombining them with UHMWPE resin prior to consolidation and irradiation.

For example, in embodiment of the invention, a first antioxidant iscombined with UHMWPE resin (that itself may have previously beencrosslinked), and consolidated to produce consolidated UHMWPE having thefirst additive. The consolidated perform may then be crosslinked at thispoint, or after the next step of adding the second additive to theconsolidated UHMWPE. In this step of this embodiment, the secondadditive is added to the consolidated UHMWPE (that has or has not beencrosslinked) by diffusion. For example, the diffusion may be byimmersion of the consolidated UHMWPE in a solution containing the secondadditive for a time sufficient for the second additive to enter theconsolidated UHMWPE to the desired amount. The second additive may alsobe diffused into the consolidated UHMWPE by exposure to the consolidatedUHMWPE to gas containing the second additive or to the second additivein a solid form, such as a fine powder uniformly laid on the UHMWPE, andheated to allow diffusion of the second additive to a desired level. Allother means of adding at least a first and a second additives to UHMWPEto produce crosslinked UHMWPE to which a first and a second additivehave been added and in which the combination of the additives produce asynergistic increase in the oxidation resistance of the crosslinkedUHMWPE are understood by one of skill in the relevant art to be withinthe scope of this invention.

Further areas of applicability of the invention will become apparentfrom the detailed description provided hereinafter. It should beunderstood that the detailed description and specific examples, whileindicating the particular embodiment of the invention, are intended forpurposes of illustration only and are not intended to limit the scope ofthe invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and form a part ofthe specification, illustrate the embodiments of the present inventionand together with the written description serve to explain theprinciples, characteristics, and features of the invention. In thedrawings:

FIG. 1 is an example flowchart describing several potential processingroutes.

FIG. 2 a is an illustration of the relationship of antioxidantconcentration (●), wear resistance (□), and oxidation resistance (▴) incrosslinked UHMWPE having a single antioxidant additive.

FIG. 2 b is an illustration of the relationship of antioxidantconcentration (●), wear resistance (□), and oxidation resistance (▴) incrosslinked UHMWPE having at least a first and a second antioxidantadditive.

FIG. 3 a is an illustration that each OIT experiment was begun with anisothermal segment at 30° C. for 10 minutes with a nitrogen flow topurge oxygen from the chamber, and where the furnace and sample werethen heated at 20° C./min to the hold temperature (T), and held for 10minutes to allow the sample and furnace to achieve equilibrium.

FIG. 3 b is an illustration of oxidation-induction-time (OIT)measurements for the Examples showing the OIT measurement.

FIG. 4 shows the oxidation-induction-time (OIT) measurements for thesamples of Example 2.

FIG. 5 shows the oxidation-induction-time (OIT) measurements for thesamples of Example 3.

FIG. 6 shows the oxidation-induction-time (OIT) measurements for thesamples of Example 4.

DETAILED DESCRIPTION OF THE EMBODIMENTS

The following description of the depicted embodiment(s) is merelyexemplary in nature and is in no way intended to limit the invention,its application, or uses. It is readily apparent to one skilled in theart that various embodiments and modifications may be made to thepresent invention without departing from the scope and spirit of theinvention.

The present invention relates to methods, products, and methods of usingproducts related to crosslinked UHMWPE that has been combined with atleast a first and at least a second antioxidant additive, wherein thecombination of the first and the second antioxidant interactsynergistically (i.e., in more than an additive manner) thereby allowingthe creation of oxidation resistant crosslinked UHMWPE (XLPE) havingimproved wear and other properties. These properties make the inventiveXLPE well suited for use in medical implants, although this is not alimitation on the claimed invention which relates to novel oxidationresistant XLPE generally. When used in medical prostheses, the XLPE maybe in the form of a bearing, for example in a prosthetic joint. Theoxidation resistant properties of the inventive XLPE make it well suitedfor use in an implant because its wear and other properties will notdeteriorate over time because the XLPE is oxidation resistant. Thisincludes that the product is not subject to oxidation during itsmanufacture and that the product does not oxidize over time. While notbeing bound or limited in any way by any theory, this long-termoxidation resistance appears to be a result of the XLPE containing atleast some antioxidant additives, or products of such additives,including compounds and products formed by interactions of the additivesand/or products of the additives in the UHMWPE.

DEFINITIONS

Unless defined otherwise, all terms, including technical and scientificterms, used herein have the same meaning as commonly understood by oneof ordinary skill in the art to which this invention belongs. Forpurposes of the present invention, the following terms have the meaningsgiven below unless otherwise indicated.

The term “ultrahigh molecular weight polyethylene” (“UHMWPE”) is wellknown in the art, which meaning is adopted herein, and generally meanspolyethylene polymers having a weight average molecular weight of about400,000 atomic mass units or more. Preferably, the ultrahigh molecularweight polyethylene has a weight average molecular weight of about1,000,000, more preferably about 2,000,000, and most preferably about3,000,000 atomic mass units or more. Typically, the weight averagemolecular weight of ultrahigh molecular weight polyethylene is less thanabout 10,000,000 atomic mass units, more preferably about 6,000,000atomic mass units or less.

The term “medical prostheses” is well known in the art, which meaning isadopted herein, and generally means a device intended to replace orsupplement part of an animal's musculoskeletal system. Common uses ofmedical prostheses within the scope of this invention include but arenot limited to artificial joints, including for example hip, knee,shoulder, finger, elbow, ankle, facet, and jaw joints. As an example,but not a limitation, XLPE may be used in medical prostheses as abearing component forming one part of a joint. For example, a UHMWPEbearing component in a prosthetic joint, such as a hip or knee joint,may be in the shape of receiving cup (such as an acetabular cup) whichprovides a surface against which another component of an artificialjoint, such as a metal or ceramic ball, articulates in the movement ofthe joint. Other uses of UHMPE in medical prostheses are expresslywithin the scope of this invention.

As used herein, term “compound(s)” means anything capable of beingdefined, identified, quantified, etc. as a single substance, and is notlimited to any more specific meaning unless clearly so-limited by thespecific context of the use of the term. Therefore, the term“compound(s)” includes but is not limited to chemical compounds,entities, molecules, complexes, agents, additives, and the like.Further, for example, unless otherwise limited by the specific contextof their use, the terms “antioxidant compound,” “antioxidant additive,”“antioxidant substance,” and “antioxidant” mean the same thing.

“Combining,” “combination,” “mixing,” “mixture,” and the like have theirordinary meanings in the art and include but are not limited to placingtwo or more agents in physical proximity to one another by, for example,admixing, blending, diffusing, compressing, mingling, comingling, andthe like. Moreover, unless the context expressly indicates otherwise,the term “combining,” “combination,” “mixing,” “mixture” and the like asused herein include combining two or more agents in any order orsequence and in any amounts.

“Irradiate,” “irradiating,” “irradiated,” and the like, as well as“radiate,” “radiating,” “radiated,” and the like, have the meaning knownin the relevant art and generally mean exposing an object (subject,article, etc.) to ionizing “radiation,” wherein the object exposed tothe ionizing “radiation” has been “irradiated,” and include but are notlimited to gamma radiation (or gamma irradiation), electron beamirradiation (or electro beam radiation), and including any dose of suchirradiation (or irradiation), and in any sequence. Further, one ofordinary skill in the relevant art understands that while there aresubtle differences between the meaning of the terms irradiation andradiation, for example as shown above (e.g., radiation is emitted from asource and the object receiving the radiation is irradiated), the termsare often used interchangeably in the relevant art to refer to the samething and unless otherwise noted, this meaning is expressly adoptedherein. Therefore, for a nonlimiting example, reference herein to anobject that “has been irradiated” means the same thing as reference toan object that “has been radiated,” or for a nonlimiting example anobject may be “irradiated” or “radiated,” wherein both meaning the samething, and so forth.

“Crosslinked,” “crosslink” and “crosslinking,” etc. in relation tocrosslinked UHMPE (also known as “XLPE”), have the meaning known in therelevant art and generally mean the formation of chemical, covalentbonds between two or more polymeric chains so as to create a molecularnetwork [e.g., 1]. “Crosslinked UHMWPE” (or “XLPE”) may be made bycrosslinking UHMWPE by any means including but not limited to byradiation or by chemical means. Radiation crosslinking of UHMWPE is wellknown in the art and generally involves the exposure of UHMWPE toionizing radiation, such as but not limited to gamma radiation or anelectron beam. The following examples are illustrative but not limiting.Mildly crosslinked UHMWPE materials can generally created duringsterilization with a gamma-radiation dose in the range of 2.5 to 4.0Mrad, which can be conducted as the last step of the process with thefinished, cleaned and packaged implant. Highly crosslinked materials canbe created through exposure to gamma radiation or an electron beam atdoses greater than 4.0 Mrad. Consolidated bars or rods are typicallyexposed to radiation to create highly crosslinked UHMWPE. Within thescope and spirit of this invention, crosslinked UHMWPE may be made bycrosslinking UHMWPE resin prior to consolidation or prior to combiningand consolidation (and may optionally be additionally crosslinked againupon crosslinking (such as by radiation) of the consolidated UHMWPEand/or a shaped implant made from the consolidated UHMWPE). Chemicalcrosslinking is well known in the art and generally includes theblending of UHMWPE resin with a peroxide [see, e.g., 2] or silane [see,e.g., 4].

“Consolidate,” and “consolidating” in the context of UHMWPE, such as“consolidating UHMWPE” have the meaning known in the art, and generallymean heating and compressing UHMWPE, which in the present invention maycontain one or more agents, and ram extruding or compression molding theUHMWPE to form “consolidated UHMWPE” which is typically in the form of abar or rod. The terms “consolidate” and “consolidated” in reference toUHMWPE generally include that the UHMWPE that has been heated andcompressed and has also been treated by the conventional step, practicedin the relevant art (and well known to one of ordinary skill in thepertinent art), of annealing after consolidating (consolidation) torelieve stress in the consolidated UHMWPE, which annealing generallyinvolves heating the UHMWPE for a determined time and temperature torelease stress caused by the compression. Thus, the term “consolidatedUHMWPE,” as used herein includes UHMWPE that has been heated andcompressed and shaped by ram extrusion or compression molding andsubsequently annealed to relieve consolidating stress.

The term “dl-alpha-tocopherol”, also known as all-rac-alpha-tocopherol,means synthetic vitamin E that is an all-racemic mixture ofapproximately equal amounts of the eight possible stereoisomers (i.e.,alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol,alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol, anddelta-tocotrienol) [see, e.g., 6]. The additive dl-alpha-tocopherol iscommercially available, for example, from Sigma-Aldrich, St. Louis, Mo.(Item T3251).

The term “curcumin” refers to, in its most pure form the compound“1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione,” alsoknown as “diferuloymethane,” that is isolated from tumeric (Curcumalonga) or has been chemically synthesized.

The term “butylated hydroxytoluene” may be abbreviated as “BHT.”

The term “butylated hydroxyanisole” may be abbreviated as “BHA.”

Synthetic antioxidant means man-made and not naturally found.

The term “synergism” has the meaning set forth below in the following 8full paragraphs (including this paragraph) and the following equations(1)-(4). The term “synergism” is known in the art related to thisinvention to mean the cooperative interaction between two or moreadditives that enhances the stabilization of a polymer by more than thesum of their individual effects [see, e.g., 9]. This meaning is setforth in the formulae below. Additionally, for purposes of clarity, theart also recognizes antagonism, which is the interaction between two ormore additives that degrades the stabilization of a polymer such thattheir combined effect is less than the sum of their individual effects.Further, the art recognizes that the balance between synergism andantagonism is an additive effect, wherein the combined effect of twoadditives is equivalent to the sum of their individual effects. Thesedefinitions are shown via the following non-limiting formulae:

If:

r_(a)=relative concentration of additive a in the combined UHMWPE,

r_(b)=relative concentration of additive b in the combined UHMWPE,

r_(n)=relative concentration of additive n in the combined UHMWPE,

where r_(a)+r_(b)+ . . . +r_(n)=1

OIT_(a)=Oxidation-induction time (OIT) of additive a alone in UHMWPE,

OIT_(b)=Oxidation-induction time (OIT) of additive b alone in UHMWPE,

OIT_(n)=Oxidation-induction time (OIT) of additive n alone in UHMWPE,and

OIT_(a,b, . . . n)=Oxidation-induction time (OIT) of additives a, b, . .. n in UHMWPEAdditive Interaction: OIT_(a,b, . . . n) =r _(a)(OIT_(a))+r_(b)(OIT_(b))+ . . . +r _(n)(OIT_(n))  (1)Synergistic Interaction: OIT_(a,b, . . . n) >r _(a)(OIT_(a))+r_(b)(OIT_(b))+ . . . +r _(n)(OIT_(n))  (2)Antagonistic Interaction: OIT_(a,b, . . . n) <r _(a)(OIT_(a))+r_(b)(OIT_(b))+ . . . +r _(n)(OIT_(n))  (3)

One of ordinary skill in the relevant art will readily understand thatthese and other specific equations for defining synergism apply inspecific situations, and that it is well within the skill of one ofordinary skill in the relevant art to modify equations to createequations specific for defining synergism under various circumstances.For example, the above equations (1)-(3) apply when the sum of theconcentrations of the additives in the combined UHMWPE together areequivalent to the concentrations of the additives in UHMWPE alone. Oneof ordinary skill in the art can readily define other equations todemonstrate synergism when this situation is not present.

As an example of this, one of the primary goals of the invention is toallow for a reduction in the concentration of the primary additive whilesimultaneously maintaining or improving the oxidation resistance of thecombined, consolidated, and crosslinked UHMWPE. Therefore, one ofordinary skill in the relevant art would know that the aforementionedequations are well suited for demonstrating synergism in this particularcase. However, it would be well within the skill of one of ordinaryskill in the art to determine equations for this (or any) situation. Forexample, to define synergism under these specific circumstances, oneskilled in the art would derive the following equation is a non-limitingexample to define synergism between two or more additives:

If:

-   -   r_(a)=relative concentration of additive a in the combined        UHMWPE,    -   r_(b)=relative concentration of additive b in the combined        UHMWPE,    -   where: r_(a)+r_(b)=1    -   C_(a)=mass concentration of additive a alone in UHMWPE,    -   C_(b)=mass concentration of additive b alone in UHMWPE,    -   OIT(C_(a))=Oxidation-induction time (OIT) of additive a alone at        concentration C_(a) in UHMWPE,    -   OIT(C_(b))=Oxidation-induction time (OTT) of additive b alone at        concentration C_(b) in UHMWPE,    -   OIT(C_(a)′,C_(b)′)=Oxidation-induction time (OIT) of additive a        at mass concentration    -   C_(a)′ and additive b at mass concentration C_(b)′ in UHMWPE    -   where: C_(a)′<C_(a),        -   C_(b)′<C_(b), and        -   C_(a)′+C_(b)′=C_(a)=C_(b)            OIT(C _(a) ′,C _(b)′)≧r _(a)[OIT(C _(a))]+r _(b)[OIT(C            _(b))]  (4)

Furthermore, it is known in the art that synergistic interaction betweentwo or more stabilizing additives or compounds (also known asstabilizer(s)) can be classified as acting through one of the followingmechanisms:

-   -   (1) Both additives react together to give a new species more        efficient in stabilization;    -   (2) A “secondary” additive reacts with the “primary” one or its        by-products to regenerate it or to inhibit deleterious effects;        and    -   (3) Both additives act at distinct levels of the radical chain        oxidation and the synergy results only from a kinetic effect.

While expressly not to be bound by theory or limited in any manner bytheory, and solely for purposes of illustration, based upon studies inthe literature, the inventors theorize that the addition of more thanone additive to crosslinked UHMWPE acts through either mechanism 2 or 3or both, depending upon the particular additives selected.

For example, previous studies have demonstrated that various additivessuch as vitamin C, catechins and polyhydric alcohols act throughMechanism 2 in combination with a phenolic antioxidant such asalpha-tocopherol. These compounds can regenerate or recycle thetocopheroxyl radical back into alpha-tocopherol and, therefore, returnthe molecule back to the original state. This, in turn, permits thealpha-tocopherol molecule to quench additional free radicals andcontinue protecting the material from oxidation.

Alternatively, phenolic antioxidants combined with sulphides orphosphites are generally believed to act through Mechanism 3, where thephenolic additives quench peroxide radicals and the sulphides orphosphites convert the hydroperoxide groups to alcohols.

Finally, some combinations of additives are believed to work throughmechanisms 2 and 3 together. For example, in blends of alpha-tocopheroland the phospite Ultranox U626 in polypropylene, the phosphite has beenreported to participate both in the deactivation of hydroperoxides(Mechanism 3) and in the regeneration of alpha-tocopherol (Mechanism 2).

The term “nominal” as used herein means the concentration of a substanceto be combined with another substance (for example, an antioxidantadditive to be combined with UHMWPE resin) wherein the amount of thesubstance to be combined with another substance is the amount of thesubstance before it is combined. For example, if a specific antioxidantadditive is to be combined with a specific amount of UHMWPE, the“nominal” concentration of the specific antioxidant would be its amountimmediately prior to combining (often, but not always or necessarily,expressed as a weight percentage of the substance into which it will becombined). This form of measurement is particularly useful where thesubstance being added to another substance may be consumed, combined,altered, reacted, or otherwise changes or become difficult to quantifyonce it is combined. However, the term “nominal” does not necessarilyrequire that a “nominal” quantity of a substance combined with anothersubstance change form or otherwise be difficult to measure and quantifyonce combined.

As used herein, the term “neat” refers to a substance that has hadnothing added to it (i.e., without additives). For a non-limitingexample, “neat GUR1020 UHMWPE” in the first line of Example 2 means thatthe GUR1020 UHMWPE has not had anything added to it at that point in theprocess (i.e., prior to combining to create Materials A, B, and/or C).

As used herein, the term “virgin” refers to a compound, combination,substance, object, and the like that has not been treated in an exampleas have been other aspects of the example, and generally refers to acontrol. For example, in Example 2, in the following sentence the term“virgin” means that the Neat GUR 1020 was not irradiated and is anunirradiated control: “Neat GUR1020 UHMWPE was consolidated, annealed torelieve residual stresses and remained in the unirradiated condition(Material D—virgin).”

The first and second additives in the present invention include but areexpressly not limited to the following examples: (1) first additives:(a) phenolic antioxidants, including (i) tocopherols, including (1)dl-alpha-tocopherol, (2) alpha-tocopherol, (3) delta-tocopherol, (4)gamma-tocopherol, and (5) beta-tocopherol, (ii) tocotrienols, including(1) alpha-tocotrienol, (2) beta-tocotrienol, (3) gamma-tocotrienol, and(4) delta-tocotrienol, (iii) curcuminoids, including (1) curcumin (i.e.,diferuloymethane), (2) demethoxycurcumin, (3) bisdemethoxycurcumin, (4)tetrahydrocurcumin, (5) hexahydrocurcumin, (6) curcumin sulphate, (7)curcumin-glucuronide, (8) hexahydrocurcuminol, and (9) cyclocurcumin,(iv) flavonoids, including (1) naringenin, (2) quercetin, (3)hesperitin, (4) luteolin, (5) catechins (including (a) epigallocatechingallate, (b) epigallocatechin, (c) epicatechin gallate, and (d)epicatechin), (6) anthocyanins (including (a) cyanidin, (b) delphinidin,(c) malvidin, (d) peonidin, (e) petunidin, and (f) pelargonidin), (v)phenylpropanoids, including (1) eugenol, (vi) synthetic antioxidants,including (1) irganox 1010, (2) irganox 1076, (3) irganox 245, (4)butylated hydroxytoluene (BHT), and (5) butylated hydroxyanisole (BHA),and (b) hindered amines, including (i) chimassorb 944, (ii) chimassorb119 FL, (iii) cyasorb UV 3346, (iv) tinuvin 144, (v) tinuvin 765, and(vi) tinuvin 770 DF; and (2) second additives: (a) phosphorouscompounds, including (i) phosphites, including (1) ultranox U626, (2)hostanox PAR24, (3) irgafos 168, (4) irgafos 126, and (5) weston 619,(ii) phosphonites, including (1) sandostab P-EPQ, (iii) phosphines,including (1) PEPFINE, (b) polyhydric alcohols, including (i)dipentaerythritol, (ii) tripentaerythritol, (iii) trimethylolpropaneethoxylate, (c) phenolic antioxidants, including (i) tocopherols,including (1) dl-alpha-tocopherol, (2) alpha-tocopherol, (3)delta-tocopherol, (4) gamma-tocopherol, (5) beta-tocopherol, (ii)tocotrienols, including (1) alpha-tocotrienol, (2) beta-tocotrienol, (3)gamma-tocotrienol, and (4) delta-tocotrienol, (iii) curcuminoids,including (1) curcumin (i.e., diferuloymethane), (2) demethoxycurcumin,(3) bisdemethoxycurcumin, (4) tetrahydrocurcumin, (5) hexahydrocurcumin,(6) curcumin sulphate, (7) curcumin-glucuronide, (8)hexahydrocurcuminol, and (9) cyclocurcumin, (iv) flavonoids, including(1) naringenin, (2) quercetin, (3) hesperitin, (4) luteolin, (5)catechins (including (a) epigallocatechin gallate, (b) epigallocatechin,(c) epicatechin gallate, and (d) epicatechin), (6) anthocyanins(including (a) cyanidin, (b) delphinidin, (c) malvidin, (d) peonidin,(e) petunidin, and (f) pelargonidin), (v) phenylpropanoids, including(1) eugenol, (vi) synthetic antioxidants, including (1) irganox 1010,(2) irganox 1076, (3) irganox 245, (5) butylated hydroxytoluene (BHT),and (6) butylated hydroxyanisole (BHA), (vii) benzoquinols, including(1) ubiquinol, and (2) coenzyme Q10, (d) hindered amines, (i) chimassorb944, (ii) chimassorb 119 FL, (iii) cyasorb UV 3346, (iv) tinuvin 144,(v) tinuvin 765, and (vi) tinuvin 770 DF, (e) carotenoids, including (i)beta-carotene, (ii) lycopene, (iii) lutein, (iv) zeaxanthin, (v)echinenone, and (iv) zeaxanthin, (f) amino-acid-based additives,including (i) glutathione, (ii) cystein, (iii) tyrosine, and (iv)tryptophan, (g) thiosynergists, including (i) distearylthiodipropionate, (ii) irganox PS 800, (iii) irganox PS 802, and (h)other additives, including (i) ascorbate, (ii) ascorbyl palmitate, and(iii) lipoic acid.

One embodiment pertains to a bearing material for a medical device thatcontains at least two types of additives that produce a synergisticeffect in scavenging of free radicals in a crosslinked polyethylene. Thepreferred antioxidant additives are Vit E and curcumin. Any othersynthetic or natural antioxidants or synergistic additives can be usedin combination to achieve such effect. For example, synergisticadditives and antioxidants could include but are not limited tocurcumin, Vit E, polyhydric alcohol, phosphites, ubiquinol-10,glutathione, ascorbic acid, anthralin, catechins such asepigallocatechin gallate, or flavonoids.

An antioxidant such as Vit E or curcumin is blended with acorresponding, synergistic additive or antioxidant and UHMWPE resin inknown concentrations. This blend is consolidated through conventionaltechniques such as ram extrusion or compression molding. Followingconsolidation, the material may be subjected to a standardstress-relieving anneal to minimize residual stresses present in thematerial. The consolidated blend is exposed to ionizing radiation (e.g.,gamma or electron beam radiation) in air or in an inert environment tocrosslink the material to produce a desired wear resistance. Due to thepresence of the antioxidant and additive, a post-irradiation heattreatment may not be necessary. A medical device, such as an orthopaedicbearing component, could then be machined from this highly crosslinked,consolidated blend and sterilized by conventional methods.

An alternative embodiment could include a medical device made of UHMWPEthat is crosslinked to 10 Mrad with a preferred ratio of Vit E tocurcumin of 1:1, but any other ratios could be used. The preferredradiation dose is from 1.5 Mrad to 30 Mrad.

Alternatively, one or more additives are blended with the resin and oneor more of the synergistic additives are diffused using a hightemperature process in the consolidated component after consolidationand either before or after crosslinking. For example, curcumin could beblended with the resin and consolidated into a preform. Aftercrosslinking, vitamin E could be diffused into either the preform or themachined implant. The diffusion process could be conducted at roomtemperature. However, for greater diffusion depths, higher temperaturesup to melting point of the polymer could be used. Thus, for example, forpolyethylene, diffusion can be carried out at 150° C. In order tominimize the deformation of the preform, lower temperatures, for example120° C., can be used. The antioxidant used for the diffusion process canbe in solid, liquid or gaseous form. For solid form antioxidant, fineground powder is uniformly laid on the preform and the whole assembly isheated to allow the antioxidant to diffuse. Alternatively, the solidantioxidant could be dissolved in a suitable solvent. For liquid formantioxidant such as alpha-tocopherol (vit E), the preform is soaked inthe liquid solution at room temperature or at elevated temperature for afew hours to several hours. The soaking time can decided based on thediffusivity of the antioxidant in the polymer and the temperature used.Higher diffusivity will allow shorter diffusion times.

In an alternative embodiment, the crosslinking is achieved using achemical crosslinking process known in the art. In such processes, oneor more additives/antioxidants could be diffused or blendedsimultaneously during crosslinking along with the crosslinking agent.Alternatively, chemical crosslinking is done after theantioxidant(s)-blended resin is consolidated.

In some embodiments, the resin is mildly crosslinked and is then blendedwith the antioxidants. After consolidation, it is again irradiated toachieve the desired level of crosslinking.

With the use of a single antioxidant in UHMWPE, the concentration mustbe carefully selected to balance both the wear resistance and theoxidation resistance with a given irradiation dose. As shown in FIG. 2a, the selection of a high level of antioxidant (Point A) inhibitscrosslinking to a greater extent, which results in decreased wearresistance (Point D). On the other hand, the higher concentration of theantioxidant provides for greater resistance to oxidation (Point E).

Since wear resistance is a primary metric of interest for crosslinkedUHMWPE in orthopaedic devices, one could choose to use a lowerconcentration of the antioxidant (Point B), which would inhibitcrosslinking to a lesser extent and provide improved wear resistance(Point C). However, the lower concentration of antioxidant available forthe long-term stabilization of the device results in degraded resistanceto oxidation (Point F).

The incorporation of a primary antioxidant with at least one secondaryadditive or antioxidant into the UHMWPE can change the relationshipsbetween these important metrics (FIG. 2 b). The interaction between thestabilizing compounds results in improved resistance to oxidation (PointK) at a lower concentration of the primary antioxidant (Point H).Because the primary antioxidant concentration is lower, the inhibitionof crosslinking is less and a given irradiation dose results in higherwear resistance (Point I).

EXAMPLES Example 1

Now referring to FIG. 1, Step 1 indicates the selection of the polymerresin or powder to be used as the starting material based upon theapplication and the required performance/properties. For example, thepolymer resin could be GUR1050 or GUR1020 ultra-high molecular weightpolyethylene (UHMWPE), Teflon, polyurethane, polyetheretherketone(PEEK), thermoplastic elastomers, etc. In Step 2, this selected polymerresin is combined with at least two synergistic additives by blending inambient conditions with standard blending/mixing techniques such asplanetary, ribbon, tumble, vertical, rotary, plow, cylindrical or bladeblending. In certain cases low molecular-weight fractions of the polymermay be used to achieve uniform distribution of the antioxidantadditives. The low molecular-weight fractions allow a lower meltingpoint constituent that may allow diffusion of antioxidant and thusuniform dispersion. As an example, lower molecular-weight fractionpolyethylene can be blended with ultra-high molecular weightpolyethylene as a starting resin. In Step 3, the blend is consolidatedinto a preform through standard techniques such as compression molded,ram extrusion, injection molding, etc. In Step 4, a standard heattreatment is conducted to relieve residual stresses generated duringconsolidation. For example, a typical post-consolidation heat treatmentfor relief of residual stresses involves heating the consolidatedmaterial in an oven or appropriate liquid bath to 104° C. or above,holding at the soak temperature, and slowly cooling the material at arate less than 6° C. per hour. Alternatively, heat treatment can be doneusing a convection-type heating oven that is heated using resistiveheating elements. Alternatively, vacuum heating can be used. In Step 5,a decision is made depending on the level of crosslinking desired in thefinal implant. If the final implant is not intended to be highlycrosslinked, Step 6 includes the machining of the desired orthopaediccomponent into the final shape. In Step 7, the implant is sterilized bygamma radiation with the standard dose of 2.5 to 4.0 Mrad (25 to 40kGy). If the final implant is intended to be highly crosslinked, Step 8describes the irradiation of a preform in air by gamma or electron-beamradiation in air with doses that range from 5 to 20 Mrad (50 to 200kGy). In Step 9, the final implant is machined from the highlycrosslinked, preform material. In Step 10, a decision is made as to thedesired method of sterilization for the highly crosslinked implant. InStep 11, the implant is sterilized by gas sterilization withoutradiation. In Step 12, the final implant is sterilized by gammaradiation with the standard dose range of 2.5 to 4.0 Mrad (25 to 40kGy).

Further referring to Example 1, and in a non-limiting manner, in oneembodiment the implant can be used as a bearing material for hiparthroplasty; in one embodiment the implant can be used as a bearingmaterial for knee arthroplasty; in one embodiment the implant can beused as a bearing material for spinal arthroplasty; and in oneembodiment can be used as a bearing material for shoulder arthroplasty.

Example 2

Neat GUR1020 UHMWPE resin was combined with the following:

-   -   Material A—dl-alpha-tocopherol (vitamin F or Vit E) at a nominal        concentration of 500 ppm (0.05 wt. %),    -   Material B—Purified curcumin, or diferuloymethane (97.7% by        HPLC), at a nominal concentration of 500 ppm (0.05 wt. %),    -   Material C—dl-alpha-tocopherol and purified curcumin at nominal        concentrations of 250 ppm (0.025 wt. %) each

It should be noted that dl-alpha-tocopherol, also known asall-rac-alpha-tocopherol, refers to synthetic vitamin E that is anall-racemic mixture of approximately equal amounts of the eight possiblestereoisomers (i.e., alpha-tocopherol, beta-tocopherol,gamma-tocopherol, delta-tocopherol, alpha-tocotrienol, beta-tocotrienol,gamma-tocotrienol, and delta-tocotrienol). These materials were thenconsolidated by compression-molding, annealed to relieve residualstresses, and subsequently gamma-irradiated with a nominal dose of 10Mrad (100 kGy). Following irradiation, no heat treatments wereconducted.

Two control materials were also evaluated. Neat GUR1020 UHMWPE wasconsolidated, annealed to relieve residual stresses and remained in theunirradiated condition (Material D—virgin). In addition, neat GUR1020UHMWPE was consolidated, annealed to relieve residual stresses,gamma-irradiated with a nominal dose of 10 Mrad (100 kGy), and re-meltedto stabilize the highly crosslinked material (Material E—10-XLPE).

To assess the oxidation resistances of these materials,oxidation-induction-time (OIT) experiments were conducted with a Netzsch204 F1 Phoenix (Huntersville, N.C.) Differential Scanning Calorimeter(DSC) in a manner similar to that described in ASTM D3895-07. Plate-likesamples were removed from the interiors of the materials, weighed to aresolution of 0.01 mg and ranged in mass from 9 to 11 mg. Each samplewas crimped in an aluminum crucible, and a hole was punched in the lidto allow for gas flow. An empty aluminum crucible with a hole in the lidwas used as the reference sample. Three samples were evaluated permaterial (n=3).

OIT experiments have been utilized to rapidly assess the oxidativestability of various polymers including a limited number of studies withUHMWPE. As shown in FIG. 3 a, each OIT experiment was begun with anisothermal segment at 30° C. for 10 minutes with a nitrogen flow rate of50 mL/min. This step was utilized to purge oxygen from the chamber andthe aluminum crucible holding the sample to avoid oxidation duringheating. The furnace and sample were then heated at 20° C./min to thehold temperature (T), which was 190° C. in this experiment, and held for10 minutes to allow the sample and furnace to achieve equilibrium (FIG.3 a). At time t₁, the nitrogen gas flow was stopped, and an oxygen flowat 50 mL/min was immediately begun. The temperature of the furnace andthe sample were held at T until an exothermic reaction was observed(FIG. 3 b), which signifies the occurrence of oxidation in the sample.The extrapolated onset time of this exotherm was determined to be t₂,and the OIT (τ) was calculated as the difference between t₁ and t₂. Theinduction time observed for additive-stabilized polymers hastraditionally been interpreted as the gradual consumption of thestabilizer, which is followed by an exothermic oxidation reaction thatis measurable in the DSC (FIG. 3 b). As a result, a greateroxidation-induction time indicates a greater resistance to oxidation.

In this experiment, the standard control materials both exhibitedoxidation-induction times of zero, which means that they oxidizedimmediately upon introduction of oxygen flow at this hold temperature(FIG. 4). In contrast, the highly crosslinked blend with 500 ppm Vit E(Material A) was found to exhibit an OIT of 3 mins, and the highlycrosslinked blend with 500 ppm curcumin (Material B) had an OIT of 10mins (FIG. 4). Based on the rule of mixtures (Equation 5) and the linearrelationship between antioxidant concentration and induction time thatis known in the art, one would expect an OIT of about 6.5 mins for a 1:1blend of Vit E and curcumin (Material C).OIT_(Mix)=0.5(OIT_(a)+OIT_(b))  (5)Where: OIT_(Mix) is the OIT for the mixture,

OIT_(a) is the OTT for substance a in UHMWPE, and

OIT_(b) is the OIT for substance b in UHMWPE.

However, the inventors have discovered that the blend with both Vit Eand curcumin (Material C) resulted in an OIT of 9 mins (FIG. 4), whichis 38% higher than might be expected, based upon Equation 5.

The mechanical properties of these materials were evaluated throughuniaxial tensile and Izod impact testing. Uniaxial tensile testing wasconducted according to ASTM D638-03. In these tests, Type IV sampleswith thicknesses of 3.0 mm were tested at 5.08 cm/min until failure.Multiple metrics are derived through this test. The yield strength (YS)of the material is defined as the transition from elastic to plasticdeformation and is generally determined to be the stress near the end ofthe linear elastic region. The ultimate tensile strength (UTS) is thehighest stress experienced by the sample during the test, and theelongation at break (EL) is the percent change in the length of thesample at the time of fracture. Izod impact testing was conductedaccording to ASTM F648-07. In this test, a standard sample of UHMWPEwith two razor-sharp notches is broken by a swinging pendulum. Theamount of energy required to break the sample is the Izod impactstrength. Therefore, a sample that requires more energy to break hasincreased toughness and a higher Izod impact strength.

Typically, the ultimate tensile strength (UTS) of UHMWPE decreases withincreasing crosslink density. Based upon this common correlation, thereduced UTS of Material C (Table 1) relative to Materials A and Bsuggests that higher levels of crosslinking have occurred in Material C.

TABLE 1 Ultimate Izod Yield Tensile Elongation Impact Strength Strengthat Strength Material (MPa) (MPa) Break (%) (kJ/m²) 500 ppm Vit E, 23.7 ±0.3 46.6 ± 2.1 280 ± 8  67 ± 1 10 Mrad (Material A) 500 ppm 23.5 ± 0.344.4 ± 3.4 264 ± 13 65 ± 2 Curcumin, 10 Mrad (Material B) 250 ppm VitE + 23.3 ± 0.4 42.8 ± 3.9 255 ± 20 66 ± 1 250 ppm Curcumin, 10 Mrad(Material C) 300 ppm Vit E + 23.7 ± 0.7 38.2 ± 4.1 234 ± 22 69 ± 2 300ppm DPE, 10 Mrad (Material F) 300 ppm 23.7 ± 0.1 40.9 ± 2.3 232 ± 10 63± 2 Curcumin + 300 ppm DPE, 10 Mrad (Material G)

Based upon these results, it is apparent that the addition of thecurcumin to the Vit E/UHMWPE blend improves the oxidation resistance ofthe material while allowing for the reduction of the Vit E content. As aresult, the irradiation dose necessary to obtain a given crosslinkdensity and wear resistance in Material C could be decreased and resultin additional improvements in the oxidation resistance. Alternatively,the irradiation dose could be maintained at 10 Mrad and result in bothimproved wear resistance and oxidation resistance compared to MaterialA.

Example 3

Neat GUR1020 UHMWPE resin was blended with the following:

-   -   Material A—dl-alpha-tocopherol (vitamin E or Vit E) at a nominal        concentration of 500 ppm (0.05 wt. %),    -   Material F—dl-alpha-tocopherol and dipentaerythritol (DPE), a        non-antioxidant polyhydric alcohol, at nominal concentrations of        300 ppm (0.03 wt. %) each.

These materials were then consolidated by compression-molding, annealedto relieve residual stresses, and subsequently gamma-irradiated with anominal dose of 10 Mrad (100 kGy). Following irradiation, no heattreatments were conducted.

Again, two control materials were also evaluated. Neat GUR1020 UHMWPEwas consolidated, annealed to relieve residual stresses and remained inthe unirradiated condition (Material D—virgin). In addition, neatGUR1020 UHMWPE was consolidated, annealed to relieve residual stresses,gamma-irradiated with a nominal dose of 10 Mrad (100 kGy), and re-meltedto stabilize the highly crosslinked material (Material E—10-XLPE). As inExample 2, the oxidation resistances of these materials were assessedthrough OIT experiments at hold temperatures of 190° C.

The standard control materials oxidized immediately upon initiation ofthe oxygen flow at 190° C. (FIG. 5), which results in an OIT of zero.UHMWPE blended with 500 ppm Vit E (Material A) resulted in an OIT of 3mins (FIG. 5). The addition of 300 ppm DPE to a blend of UHWMPE withonly 300 ppm Vit E (Material F) resulted in an OIT of 8 minutes, whichrepresents an increase of 166%. Thus, the addition the second additive,DPE, with the Vit E improved the oxidation resistance while allowing theconcentration of Vit E to be decreased by 40%, which will result inimproved crosslinking efficiency. This improved oxidation resistanceoccurs despite the fact that DPE is not known to be an antioxidant andwould, therefore, in theory exhibit an OIT of zero if combined withUHMWPE alone. The reduced ultimate tensile strength (UTS) of Material Frelative to Material A suggests higher levels of crosslinking inMaterial F (Table 1). As a result, the irradiation dose necessary toobtain a given crosslink density and wear resistance could be decreased,which will also result in improved oxidation resistance and mechanicalproperties, particularly ductility and toughness, relative to MaterialA.

Alternatively, one could decrease the Vit E concentration further in theVit E/DPE blend to provide improved wear resistance in combination withoxidation resistance equivalent to Material A.

Example 4

Neat GUR1020 UHMWPE resin was blended with the following.

-   -   Material B—Purified curcumin, or diferuloymethane (97.7% by        HPLC), at a nominal concentration of 500 ppm (0.05 wt. %),    -   Material G—Purified curcumin, or diferuloymethane (97.7% by        HPLC), and dipentaerythritol (DPE), a non-antioxidant polyhydric        alcohol, at nominal concentrations of 300 ppm (0.03 wt. %) each.

These materials were then consolidated by compression-molding, annealedto relieve residual stresses, and subsequently gamma-irradiated with anominal dose of 10 Mrad (100 kGy). Following irradiation, no heattreatments were conducted.

Again, two control materials were also evaluated. Neat GUR1020 UHMWPEwas consolidated, annealed to relieve residual stresses and remained inthe unirradiated condition (Material D—virgin). In addition, neatGUR1020 UHMWPE was consolidated, annealed to relieve residual stresses,gamma-irradiated with a nominal dose of 10 Mrad (100 kGy), and re-meltedto stabilize the highly crosslinked material (Material E—10-XLPE). As inExample 2, the oxidation resistances of these materials were assessedthrough OIT experiments at hold temperatures of 190° C.

The standard control materials oxidized immediately upon initiation ofthe oxygen flow at 190° C. (FIG. 6), which results in an OIT of zero.Material B exhibited an OIT of 10 mins (FIG. 6). The addition of 300 ppmDPE to a blend of UHWMPE with only 300 ppm curcumin (Material G)resulted in oxidation resistance that is approximately equivalent tothat of Material B. This improved oxidation resistance occurs despitethe fact that DPE is not known to be an antioxidant and would,therefore, in theory exhibit an OIT of zero if combined with UHMWPEalone. The decrease in UTS for Material G (Table 1) suggests that agreater degree of crosslinking was obtained, which would result inimproved wear resistance. Alternatively, one could irradiate theMaterial G with a lower gamma-radiation dose to achieve equivalent wearresistance, similar UTS and improved oxidation resistance relative toMaterial B.

As various modifications could be made to the exemplary embodiments, asdescribed above with reference to the corresponding illustrations,without departing from the scope of the invention, it is intended thatall matter contained in the foregoing description and shown in theaccompanying drawings shall be interpreted as illustrative rather thanlimiting. Although the majority of examples described here are relatedto UHMWPE, any other polymer could be used. Thus, the breadth and scopeof the present invention should not be limited by any of theabove-described exemplary embodiments, but should be defined only inaccordance with the following claims appended hereto and theirequivalents.

REFERENCES

With the exception of the priority application (U.S. Provisional PatentApplication No. 61/175,308, filed May 4, 2009, to which this applicationclaims priority and which application is incorporated herein byreference in its entirety), the patents, patent applications, andpublications mentioned in the specification are indicative of the levelsof skill those of ordinary skill in the art to which the inventionpertains. They are also intended to illustrate in a strictlynon-limiting manner that which was known at the time of the invention tothose of ordinary skill in the art to which the invention pertains. Theyare not intended to limit the invention described herein in any manner.

-   [1] L. Costa and P. Bracco, “Mechanisms of crosslinking, oxidative    degradation and stabilization of UHMWPE,” in UHMWPE Biomaterials    Handbook, S. M. Kurtz, Ed., Burlington, Mass.: Elsevier, 2009.-   [2] F. W. Shen, H. A. McKellop, and R. Salovey, “Irradiation of    chemically crosslinked ultrahigh molecular weight polyethylene,” J    Polym Sci B, 1996; 34:1063-1077.-   [3] M. Nakris, A. Tzur, A. Vaxman, H. G. Fritz, “Some properties of    silane-grafted moisture-crosslinked polyethylene,” Polym Eng Sci,    1985; 25(13):857-862.-   [4] S. Al-Malaika and S. Issenhuth, “Processing effects on    antioxidant transformation and solutions to the problem of    antioxidant migration,” in Polymer Durability: degradation,    stabilization, and lifetime prediction, R. L. Clough, N. C.    Billingham and K. T. Gillen, Eds., Washington D.C.: American    Chemical Society, 1996.-   [5] F. Gugumus, “Possibilities and limits of synergism with light    stabilizers in polyolefins 1. HALS in polyolefins,” Polym Degrad    Stabil, 2002; 75(2):295-308.

As various modifications could be made to the exemplary embodiments, asdescribed above with reference to the corresponding illustrations,without departing from the scope of the invention, it is intended thatall matter contained in the foregoing description and shown in theaccompanying drawings shall be interpreted as illustrative rather thanlimiting. Although the majority of examples described here are relatedto UHMWPE, any other polymer could be used. Thus, the breadth and scopeof the present invention should not be limited by any of theabove-described exemplary embodiments, but should be defined only inaccordance with the following claims appended hereto and theirequivalents.

Further, although the present invention and its advantages have beendescribed in detail, it should be understood that various changes,substitutions and alterations can be made herein without departing fromthe invention as defined by the appended sentences and descriptions.Moreover, the scope of the present application is not intended to belimited to the particular embodiments of the process, machine,manufacture, composition of matter, means, methods, or steps presentlyexisting or later to be developed that perform substantially the samefunction or achieve substantially the same result as the correspondingembodiments described herein may be utilized or wherein any differencesare insubstantial. Accordingly, the appended statements are intended toinclude within their scope such processes, machines, manufacture,compositions of matter, means or steps.

What is claimed is:
 1. A process for preparing crosslinked oxidationresistant UHMWPE for medical prostheses comprising the steps of: (i)obtaining UHMWPE resin; (ii) combining the UHMWPE resin with both afirst amount of a first additive and a second amount of a secondadditive, wherein the first and the second additives are differentadditives; (iii) consolidating the UHMWPE that has been combined withthe first and second additives; (iv) heat treating the consolidatedUHMWPE and (v) crosslinking the consolidated UHMWPE to create oxidationresistant UHMWPE, wherein the first and second additives synergisticallyincrease the oxidation resistance of the crosslinked UHMWPE, wherein theamount of the first additive that is combined with the UHMWPE in step(ii) is about 50 ppm to about 5,000 ppm, and wherein the amount of thesecond additive that is combined with the UHMWPE in step (ii) is about50 ppm to about 5,000 ppm.
 2. A medical prosthesis comprising a bearingcomponent comprising crosslinked UHMWPE made by the process of claim 1.3. A medical prosthetic bearing component made by the process ofclaim
 1. 4. The process of claim 1, further comprising the step ofmachining the oxidation resistant UHMWPE into a bearing component for amedical prosthesis.
 5. The process of claim 4, wherein the crosslinkdensities of the oxidation resistant and machined UHMWPE bearingcomponent are about 0.03 mol/dm³ to about 0.50 mol/dm³.
 6. The processof claim 1, wherein the first additive is selected from the groupconsisting of phenolic antioxidants and hindered amines, and the secondadditive is selected from the group consisting of phosphorous additives,polyhydric alcohols, phenolic antioxidants, hindered amines,carotenoids, amino-acid-based additives, thiosynergists, and acidantioxidants.
 7. The process of claim 1, wherein the crosslinking isselected from the group consisting of irradiation crosslinking andchemical crosslinking.
 8. The process of claim 1, wherein thecrosslinking is irradiation crosslinking.
 9. The process of claim 8,wherein the dose of the crosslinking is about 1.5 MRad to about 30 MRad.10. The process of claim 1, wherein the first additive isdl-alpha-tocopherol and the second additive is curcumin.
 11. The processof claim 10, wherein the first additive dl-alpha-tocopherol is combinedwith the UHMWPE in step (ii) at about 500 ppm; the second additivecurcumin is combined with the UHMWPE in step (ii) at about 500 ppm; andthe crosslinking in step (v) is by irradiation at a dose of about 10MRad.
 12. The process of claim 1, wherein the first additive isdl-alpha-tocopherol and the second additive is dipentaerythritol. 13.The process of claim 12 wherein the first additive dl-alpha-tocopherolis combined with the UHMWPE in step (ii) at about 300 ppm; the secondadditive dipentaerythritol is combined with the UHMWPE in step (ii) atabout 300 ppm; and the crosslinking in step (v) is by irradiation at adose of about 10 MRad.
 14. The process of claim 1, wherein the firstadditive is curcumin and the second additive is dipentaerythritol. 15.The process of claim 14, wherein the first additive curcumin is combinedwith the UHMWPE in step (ii) at about 300 ppm; the second additivedipentaerythritol is combined with the UHMWPE in step (ii) at about 300ppm; and the crosslinking in step (v) is by irradiation at a dose ofabout 10 MRad.
 16. The process of claim 1, wherein the crosslinking ischemical crosslinking, and wherein at least one of the first additiveand the second additive is added or combined simultaneously with acrosslinking agent during said crosslinking.
 17. The process of claim 1,wherein said crosslinking comprises a first stage comprising mildlycrosslinking the UHMWPE resin prior to said combining, consolidating andadding, and a second stage of crosslinking after said consolidating.